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`
`Editor-in-Chief:
`Mohamad Said Maani Takrouri
`(KSA)
`
`For entire EdilDrilll l!ollrd viii! :
`
`Anesthesia: Essays and
`Researches
`
`Review Article
`Current role of dexmedetomidine in clinical anesthesia
`and intensive care
`
`Manpreet Kaur, P. M. Singh 1
`
`Department of Anaesthesia and Critical Care, All India Institute of Medical Sciences, J.P.N.A Trauma Centre, 1Department of Anaesthesia and
`Critical Care, All India Institute of Medical Sciences, New Delhi, India
`
`Corresponding author: Dr. Manpreet Kaur, Department of Anaesthesia, All India Institute of Medical Sciences, J.P.N.A Trauma Centre, New Delhi - 110 029, India.
`E-mail: manpreetkaurrajpal@yahoo.com
`
`Abstract
`
`Dexmedetomidine is a new generation highly selective a.2-adrenergic receptor (a.2-AR) agonist that
`is associated with sedative and analgesic sparing effects, reduced delirium and agitation, perioperative
`sympatholysis, cardiovascular stabilizing effects, and preservation of respiratory function. The aim of
`this review is to present the most recent topics regarding the advantages in using dexmedetomidine
`in clinical anesthesia and intensive care, while discussing the controversial issues of its harmful effects.
`
`Key words: Dexmedetomidine, intensive care unit sedation, a.2-adrenergic receptor agonist
`
`ICU patient management,131 it has been studied in several
`other perioperative settings, which will be discussed.
`
`CHEMICAL STRUCTURE
`
`Dexmedetomidine is the dextrorotatory S-enantiomer of
`medetomidine, an agent used in veterinary medidne.141
`It
`is chemically (S)-4-[1-(2,3-dimethylphenyl) ethyl]-3H(cid:173)
`imidazole [Figure 1 ].
`
`INTRODUCTION
`
`(a.2-AR) agonists have been
`receptor
`a.2-adrenergic
`successfully used
`in several clinical settings
`in view
`of diverse actions which
`include sedation, analgesia,
`anxiolysis, perioperative
`sympatholysis, cardiovascular
`stabilizing effects, reduced anesthetic requirements, and
`preservation of respiratory function.Pl Dexmedetomidine
`is a relatively new drug approved at the end of 1999 by
`the Food and Drug Administration (FDA) for humans use
`for short-term sedation and analgesia ( <24 hours) in the
`intensive care unit (ICU). Dexmedetomidine is a useful
`sedative agent with analgesic properties, hemodynamic
`stability and ability to recover respiratory function in
`mechanically ventilated patients facilitating early weaning.121
`Besides being a new modality of sedation and analgesia in
`
`Website
`
`Access this article online
`DOI
`
`Quick Response Code
`
`www.aeronline.org
`
`10.4103/0259-1162.94750
`
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`.
`
`Figure I: Chemical structure of dexmedetomidine
`
`Hospira, Exh. 2012, p. 1
`
`

`
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`Anesthesia: Essays and Researches; 5(2);Jul-Dec 2011
`
`Kaur and Singh: Current role of dexmedetomidine in clinical anesthesia and intensive care
`
`MECHANISM OF ACTION
`
`a2-AR agonists produce clinical effects after binding
`to G-Protein-coupled a2-AR, of which there are three
`subtypes (a2A, a2B, and a2C) with each having
`different physiological functions and pharmacological
`activities. These
`receptor
`subtypes
`are
`found
`ubiquitously in the central, peripheral, and autonomic
`nervous systems, as well as in vital organs and blood
`vessels.151 Dexmedetomidine is 8 to 10 times more
`than clonidine.16
`1 Neither
`selective
`towards a2-AR
`clonidine nor dexmedetomidine is totally selective for
`any one of the a2-AR subtypes, but dexmedetomidine
`seems to have higher a2A-AR and a2C-AR affinity than
`1 Major differences in the pharmacology of
`clonidine.17
`clonidine and dexmedetomidine have been described in
`[Table 1].
`
`Locus ceruleus of the brain stem is the principal site for
`the sedative action and spinal cord is the principal site for
`the analgesic action, both acting through a2A-AR. In the
`heart, the dominant action of a2-AR agonists is a decrease
`in tachycardia (through blocking cardioaccelerator nerve)
`and bradycardia via a2A-AR (through a vagomimetic
`action).
`In
`the peripheral vasculature,
`there
`is
`sympatholysis-mediated
`vasodilatation
`and
`smooth
`muscle cells receptor-mediated vasoconstriction.18
`1 The
`mechanism for the antishivering and diuretic actions has
`yet to be established firmly191 [Figure 2].
`
`The responses to activation of the receptors in other
`areas include decreased salivation, decreased secretion,
`and decreased bowel motility in the gastrointestinal
`
`Table I: Comparison of clonidine with
`dexmedetomidine
`Clonidine
`Developed in the 1960s
`Clinically used first as
`antihypertensive in 1966
`
`Dexmedetomidine
`Developed in the 1980s
`Clinically approved as sedative and
`analgesic used in ICU in 1999
`Dexmedetomidine is 7-8 times
`more specific for a2.
`Ratio a. 2:a. I receptor binding is
`1620:1
`Dexmedetomidine is a full agonist
`at the a. 2 adrenergic receptor
`Octanol/buffer partition
`coefficient: 2.8 more lipophilic
`(3.5-fold) than donidine
`Dexmedetomidine has been
`shown to result in approximately
`a 90% reduction in inhalational
`anesthetic requirement to
`maintain I MAC
`Plasma half-life TV2: 2-2.5 hours
`Protein binding: 94%
`Elimination half life is 2 hrs
`Distribution half life is 5 min
`
`Ratio a. 2:a. I receptor binding
`is 220:1
`
`Clonidine is a partial agonist at
`the a. 2 adrenergic receptor
`Octanol/buffer partition
`coefficient: 0.8
`
`The maximum reduction
`in inhalational anesthetic
`requirement to maintain I MAC
`provided by clonidine is 50%
`
`Plasma half-life is TV2: 9-12 hours
`Protein binding: 50%
`Elimination half life is 8 hrs
`Distribution half life is > I 0 min
`
`tract; contraction of vascular and other smooth muscle;
`inhibition of renin release, increased glomerular filtration,
`and increased secretion of sodium and water in the
`kidney; decreased intraocular pressure; and decreased
`insulin release from the pancreas.11°1 Combining all these
`effects, dexmedetomidine avoids some of the side effects
`of multiagent therapies.
`
`PHARMACOKINETICS
`
`Absorption and distribution
`Dexmedetomidine exhibits linear pharmacokinetics in
`the recommended dose range of 0.2 to 0. 7 µg/kg/hr
`administered as intravenous infusion up to 24 hours.
`The distribution phase is rapid, with a half-life of
`distribution of approximately 6 minutes and elimination
`half life of 2 hours. The steady-state volume of
`distribution is 118 L. The average protein binding
`is 94% and is constant across the different plasma
`concentrations and also similar in males and females.
`It has negligible protein binding displacement by
`drugs commonly used during anesthesia and in the
`ICU like fentanyl, ketorolac, theophylline, digoxin, and
`lidocaine.1101 Context-sensitive half life ranges from
`4 minutes after a 10-minute infusion to 250 minutes
`is
`after an 8-hour
`infusion. Oral bioavailability
`poor because of extensive
`first-pass metabolism.
`However, bioavailability of sublingually administered
`dexmedetomidine is high (84%), offering a potential
`role in pediatric sedation and premedication.11 1
`1
`
`Metabolism and excretion
`complete
`almost
`Dexmedetomidine
`undergoes
`biotransformation
`through
`direct N-glucuronidation
`and cytochrome P-450
`(CYP 2A6)-mediated aliphatic
`hydroxylation to inactive metabolites. Metabolites are
`excreted in the urine (about 95%) and in the feces (4%).1101
`Dose adjustments are required in patients with hepatic
`failure because of lower rate of metabolism.
`
`Vasoconstriction
`a2B-AR
`
`Vasodilation
`a2-AR
`
`~ a
`Vt® V
`
`Diuresis
`? a2B-AR
`
`Analgesia
`a2A-AR
`
`Figure 2: Physiology of various a.2-adrenergic receptors
`
`Hospira, Exh. 2012, p. 2
`
`

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`[PDF Purchased from http:/!www.aeronline.org on Wednesday, November 09, 2016]abce
`
`Anesthesio: Es.soys ond Reseorches; 5(2); Jul-Dec 2011
`
`Kaur and Singh: Current role of dexrnedetomidine in clinical anesthesia and intensive care
`
`CLINICAL PHARMACOLOGY
`
`Cardiovascular system
`Dexmedetomidine evokes a biphasic blood pressure
`response: A short hypertensive phase and subsequent
`hypotension. The two phases are considered to be mediated
`by two different a.2-AR subtypes: the cx-28 AR is responsible
`for the initial hypertensive phase, whereas hypotension
`is mediated by the cx2A-AR.1121 In younger patients with
`high levels of vagal tone, bradycardia and sinus arrest
`have been desaibed which were effectively treated with
`anticholinergic agents (atropine, glycopyrrolate).
`
`Central nervous system
`flow and
`Dexmedetomidine
`reduces cerebral blood
`cerebral metabolic requirement of oxygen but its effect on
`intracranial pressure (ICP) is not yet dear. Dexmedetomidine
`modulates spatial working memory, enhancing cognitive
`performance besides having sedative, analgesic, and
`anxiolytic action through the a.2-AR.1131 Studies suggest
`the likelihood of its neuroprotective action by reducing
`the levels of cirrulating and brain catecholamines and thus
`balancing the ratio between cerebral oxygen supplies,
`reducing excitotoxicity, and
`improving
`the perfusion
`in the ischemic penumbra. It reduces the levels of the
`glutamate responsible for cellular brain injury, especially
`in subarachnoid hemorrhage.1141 It has been shown to limit
`the morphologic and functional effects after ischemic (focal
`and global) and traumatic injury to the nervous system.
`
`Respiratory effects
`Dexmedetomidine affect on respiration appears to be similar
`in order of magnitude to those seen in the heavy sleep
`state,1151 Dexmedetomidine does not suppress respiratory
`fimction, even at high doses.116J It has no adverse effects
`on respiratory rate and gas exchange when used in
`spontaneously breathing ICU patients after surgery.1151 It helps
`in maintaining sedation without cardiovascular instability
`or respiratory drive depression and hence may facilitate
`weaning and extubation in trauma/surgical ICU patients
`who have failed previous attempts at weaning because of
`agitation and hyperdynamic cardiopulmonary response.'2·171
`
`Endocrine and renal effects
`Dexmedetomidine activates peripheral presynaptic a.2-AR
`which reduces the release of catecholamines, and hence
`reduces sympathetic response
`
`to surgery.1111 Animal
`studies have demonstrated the occurrence of natriuresis
`and diuresis. Dexmedetomidine is an imidazole agent
`but unlike etomidate, it does not appear to inhibit
`steroidogenesis when used as an infusion for short-term
`sedation.1191
`
`ADVERSE EFFECTS
`
`The various reported side effects are hypotension,
`hypertension, nausea, vomiting, dry mouth, bradycardia,
`
`chills, pleural effusion,
`fibrillation, pyrexia,
`atrial
`edema,
`hyperglycemia,
`atelectasis,
`pulmonary
`etc. Rapid
`administration
`hypocalcaemia,
`acidosis,
`of dexmedetomidine
`infusion
`(Loading
`dose of
`1 µ/kg/hr if given in less than 10minutes) may cause
`transient hypertension mediated by peripheral a2B-AR
`vasoconstriction.151 But hypotension and bradycardia
`may occur with ongoing therapy mediated by central
`a2A-AR, causing decreased release of noradrenaline
`from
`the sympathetic nervous
`system. Long-tenn
`use of dexmedetomidine leads to super sensitization
`and upregulation of
`receptors;
`so, with abrupt
`discontinuation, a withdrawal syndrome of nervousness,
`agitation, headaches, and hypertensive crisis can occur.1201
`Dexmedetomidine is not recommended in patients with
`advanced heart block and ventricular dysfunction.151 FDA
`has classified it as a category C pregnancy risk, so the
`drug should be used with extreme caution in women who
`are pregnant.
`
`CLINICAL APPLICATIONS OF DEXMEDETOMIDINE
`
`Premedication
`for
`adjuvant
`an
`as
`used
`is
`Dexmedetomidine
`to
`premedication, especially
`in patients susceptible
`preoperative and perioperative stress because of its
`sedative, anxiolytic, analgesic, sympatholytic, and stable
`hemodynamic
`profile. Dexmedetomidine
`decreases
`oxygen consumption in intraoperative period (up to 8%)
`and in postoperative period (up to 17%).1211 Premedication
`dose is 0.33 to 0.67 mg/kg IV given 15 minutes before
`surgery (this dose minimizes side effects of hypotension
`and bradycardia).
`
`Intraoperative use
`hemodynamic
`attenuates
`Dexmedetomidine
`intubation and extubation by
`to
`stress
`response
`In view of absent
`respiratory
`sympatholysis.115•2:z.241
`depression, it can be continued at extubation period
`unlike
`other drugs. Dexmedetomidine potentiates
`anesthetic effect of all the anesthetic agents irrespective
`of the mode of administration (intravenous, inhalation,
`of
`regional
`block).
`lntraoperative
`administration
`dexmedetomidine in lower concentrations has reduced
`the requirement of other anesthetic agents; fewer
`interventions to treat tachycardia; and a reduction in
`the incidence of myocardial ischemiaJl31 However, side
`effects like bradycardia and hypotension are limitations
`to its use necessitating need for pharmacological rescue
`therapy. These effects may be attributed to the combined
`properties of volatile anesthetics such as vasodilatation and
`myocardial depression. Dexmedetomidine administered
`in high concentrations may cause systemic and pulmonary
`hypertension because of direct peripheral vascular effects
`or may compromise myocardial function and blood
`pressure.
`
`Hospira, Exh. 2012, p. 3
`
`

`
`[PDF Purchased from http:/!www.aeronline.org on Wednesday, November 09, 2016]abce
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`Anesthesio: Es.soys ond Reseorches; 5(2): Jul-Dec 2011
`
`Kaur and Singh: Current role of dexrnedetomidine in clinical anesthesia and intensive care
`
`Locoregional analgesia
`Highly lipophilic nature of dexmedetomidine allows rapid
`absorption into the cerebrospinal fluid and binding to
`a2-AR of spinal cord for its analgesic action. It prolongs
`the duration of both sensory and motor blockade
`induced by local anesthetics irrespective of the route of
`administration (e.g., epidural,1251 caudal,1261 or spinall271).
`Dexmedetomidine though enhances both central and
`local anesthetics;127J
`peripheral neural blockade by
`however, the peripheral neural blockade is due to
`its binding to a2A-AR.1281 Dexmedetomidine has been
`successfully used
`in
`intravenous regional anesthesia
`(IVRA),1291 brachia! plexus block,1301 and intraarticularly.131.321
`Addition of 0.5 µg/kg dexmedetomidine to lidocaine
`for IVRA improves quality of anesthesia and improves
`intraoperative-postoperative analgesia without causing
`side effects.1291 Dexmedetomidine added to levobupivacaine
`for axillary brachia! plexus block shortens the onset time
`and prolongs the duration of the block and postoperative
`analgesia.1301 Intraarticular dexmedetomidine in patients
`undergoing arthroscopic knee surgery improves the
`quality and duration of postoperative analgesia.l31.a21
`
`Sedation in intensive care unit
`Dexmedetomidine has become popular sedative agent in ICU
`because of its ability to produce cooperative sedation, i.e.,
`patients remain awake, calm, and are able to communicate
`their needs. It does not interfere with the respiratory drive
`or produce any agitation, hence facilitating early weaning
`from ventilator, thereby reducing overall ICU stay costs.1331
`The maintenance of natural sleep during sedation might
`speed recovery time in the ICU. Dexmedetomidine currently
`is approved by FDA for use in ICU for not more than
`24 hours; though many studies have reported its safe use
`for longer duration.1341 Dexmedetomidine, when compared
`with coiwentional sedatives and opiates [Pclble 2], has been
`demonstrated to be associated with both sedative and
`analgesic sparing effects, reduced delirium and agitation,
`minimal respiratory depression, and desirable cardiovascular
`effects.12.35.361
`
`Procedural sedation
`short(cid:173)
`for
`Dexmedetomidine
`is an attractive agent
`tenn procedural sedation and has been safely used in
`transesophageal
`echocardiography,1371
`colonoscopy,1381
`awake carotid endarterectomy,1391 shockwave lithotripsy,!341
`vitreoretinal surgery,140J elective awake fiberoptic intubation,1411
`pediatric patients undergoing tonsillectomy,1421 and pediatric
`MRJ.1'431 The usual dose of dexmedetomidine for procedural
`sedation is 1 µg,rkg, followed by an infusion of 0.2 µg/kglh.
`Its onset of action is less than 5 minutes and the peak effect
`ocrur within 15 minutes. As the pharmacologic effects of
`dexmedetomidine can be reversed by the cx2-AR antagonist
`atipamezole,1441 dexmedetomidine provides a titratable fonn
`of hypnotic sedation that can be readily reversed.
`
`Controlled hypotension
`Dexmedetomidine
`is an effective and safe agent for
`controlled hypotension mediated by its central and peripheral
`sympatholytic action. Its easy administration, predictability
`with anesthetic agents, and lack of toxic side effect while
`maintaining adequate perfusion of the vital organs makes
`it a near-ideal hypotensive agent Spinal fusion surgery
`for idiopathic scoliosis,1451 septoplasty and tympanoplasty
`operations,1461 and maxillofacial surgeryl47J have been safely
`done with dexmedetomidine-controlled hypotension.
`
`Analgesia
`Dexmedetomidine activates a2-AR in the spinal cord
`reducing
`transmission of nociceptive
`signals
`like
`substance P. It has significant opioid sparing effect and is
`useful in intractable neuropathic pain.1141
`
`Cardiac surgery
`the
`blunting
`to
`addition
`in
`Dexmedetomidine
`hemodynamic response to endotracheal intubation also
`reduces the extent of myocardial ischemia during cardiac
`has
`been
`successfully
`surgery.1481 Dexmedetomidine
`used to manage patients with pulmonary hypertension
`undergoing mitral valve replacement, with reduction in
`pulmonary vascular resistance, pulmonary artery pressure,
`and pulmonary capillary wedge pressures.151
`
`Table 2: Comparison of dexmedetomidine with other ICU sedatives
`Effects
`Dexmedetomidine
`Benzodlazepines
`Propofol
`v
`v
`v
`~~
`v
`Analgesia
`v
`v
`Alleviation of anxiety
`v
`Cooperative sedation
`v
`Facilitation ohentilation
`during weaning
`No respiratory depression
`Control of delirium
`Organ protection
`Control of stress response
`Antishivering agent
`Mimickirc of natural sleep
`
`Opioids
`v
`v
`
`Haloperidol
`v
`
`Based on data from
`Pandharipande et o/)UJ
`
`Hospira, Exh. 2012, p. 4
`
`

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`
`Anest#IWo: Essays ond Reseorches; S(2);Jul-Dec 2011
`
`Kaur and Singh: Current role of dexmedetomidine in clinical anesthesia and intensive care
`
`Neurosurgery
`Dexmedetomidine provides stable cerebral hemodynamics
`without sudden
`increase
`in
`ICP during
`intubation,
`extubation, and head pin
`insertion.
`It attenuates
`neurocognitive
`impairment
`(delirium and agitation)
`allowing
`immediate
`postoperative
`neurological
`evaluation. It exerts its neuroprotective effects through
`several mechanisms which make the usage of this drug
`a promising tool during cerebral ischemia.1141 It does
`not interfere with neurological monitorsl51 and has an
`upcoming role in "functional" neurosurgery. This includes
`awake craniotomy for the resection of tumors or epileptic
`foci in eloquent areas, and the implantation of deep brain
`stimulators for Parkinson's disease.151
`
`Obesity
`Dexmedetomidine does not cause respiratory depression
`and has been infused at a dose of 0. 7 µg/kg intraoperatively
`to avoid respiratory depression due to narcotic usage in a
`morbidly obese patient.1491
`
`Obstetrics
`Dexmedetomidine has been successfully used as an
`adjunct to unsatisfactory analgesia by systemic opioids in
`laboring parturients who could not benefit from epidural
`analgesia.1501 It provides maternal hemodynamic stability,
`anxiolysis, and stimulation of uterine contractions. It
`is retained in placental tissue and passes less readily
`into the fetal circulation than clonidine because of high
`lipophilicity and thereby has less susceptibility to cause
`fetal bradycardia.
`
`Pediatrics
`It is currently being used off-label as an adjunctive agent
`in pediatric patients for sedation and analgesia in the
`critical care unit and for sedation during noninvasive
`procedures in radiology like computed tomography and
`magnetic resonance imaging,1431
`
`for
`
`Other uses
`suggests other potential uses
`The
`literature
`dexmedetomidine, for example
`• Dexmedetomidine has been used successfully in
`the treatment of withdrawal from benzodiazepines,
`opioids, alcohol, and recreational drugs.
`• As an adjunct in otorhinolaryngology anesthesia for
`middle ear surgery and rhinoplasty.
`• As an adjunct in the repair of aortic aneurysms.
`• Management of tetanus in ICU.
`• As an antishivering agent.
`• Dexmedetomidine is effective in preventing ethanol(cid:173)
`induced neurodegeneration.
`
`CONCLUSION
`
`Dexmedetomidine because of its unique properties offers
`its promising use in wide spectrum of clinical settings and
`
`ICUs. It is a part of fast-tracking anesthesia regimens and
`offers anesthetic sparing and hemodynamic stabilizing
`effects. As pharmacological effects of dexmedetomidine
`can be reversed by a2-AR antagonist atipamezole,
`combination of dexmedetomidine and atipamezole can
`provide titratable form of sedation in the future.
`
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`Anesthesio: &soys ond Reseorc:hes; 5(2); Jul-Dec 20 I I
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`
`How to cHe this artlcle: Kaur M, Singh PM. Current role of
`dexmedetomidine in clinical anesthesia and intensive care.
`Anesth Essays Res 2011 ;5:128-33.
`Source of Support: Nil, Confllct of Interest: None declared.
`
`Hospira, Exh. 2012, p. 6